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Aggressive Ovarian Cancer May Be Caused by a Single Gene Mutation

Researchers have identified a genetic mutation that appears to cause a rare but very aggressive type of ovarian cancer in young women.

Memorial Sloan Kettering researchers have identified a genetic mutation that appears to cause a rare but very aggressive type of ovarian cancer in young women. The discovery could be an important step toward developing the first effective treatments for the disease, called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Funded initially by a charitable organization, the research is also an example of the powerful effect philanthropy can have on rare diseases.

“There are many examples of women in their late teens or early 20s dying quickly from this disease,” says gynecologic oncologist Douglas Levine, who led the research. “The median age at diagnosis is 23, and they usually die within two years — it’s devastating. Finding the cause and a possible target could be a major advance because current therapies have very little effect.”

The discovery was made through the genetic analysis of tumor samples from 12 patients with SCCOHT. Memorial Sloan Kettering genomics researcher Michael Berger sequenced 279 genes that have been implicated in the development or behavior of tumors. This approach, called IMPACT, found that all 12 samples had a mutation in a gene called SMARCA4.

Using human cancer cells, Dr. Levine and colleagues then demonstrated that SMARCA4 plays a functional role in promoting or blocking cancer growth. Inactivating SMARCA4 increased cancer growth, while boosting its expression slowed it down. This buttresses the theory that the SMARCA4 mutation is key to the rare disease.

“I don’t know of many cancers where there’s one gene that is universally mutated and seems to be driving the disease,” Dr. Levine says. “One of our next steps will be to investigate whether this one mutation is actually sufficient to transform any type of ovarian cell into a cancer cell, or whether other factors are involved.”

The Role of Chromatin Remodeling

SMARCA4 helps regulate a biological process called chromatin remodeling. Chromatin is the complex of DNA and protein that packages a cell’s genetic material into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged — which in turn affects how a gene is expressed.

“An increasing number of chromatin remodeling genes are being associated with cancer, and there’s a growing appreciation of chromatin’s role in the disease,” Dr. Levine explains.

The researchers also plan to develop potential therapies and test them on cell lines that carry the SMARCA4 mutation. “Now that we know the target — what we think is the Achilles’ heel — we’ll try to hit it,” Dr. Levine says.

Overcoming Research Hurdles

Conducting research on SCCOHT has been exceptionally challenging due to the disease’s rarity. Dr. Levine and his colleagues initially had only three tumor samples from Memorial Sloan Kettering patients. In order to round up enough samples for a more conclusive finding, they contacted a patient group — the Small Cell Ovarian Cancer Foundation — and had a request posted on the group’s website. Slowly, nine more samples trickled in, one from as far away as Spain.

In addition, securing funding to do the genetic analysis on such a rare tumor type was difficult. Dr. Levine credits the critical support of the Katie Oppo Research Fund, an organization founded to increase awareness of and fund research into SCCOHT. Based in Manhasset, New York, on Long Island, the fund was established in honor of Katie Oppo, who died from SCCOHT in 2011 at the age of 19, only eight months after she had been diagnosed.

Katie’s mother, Liz Oppo, leads the organization and was directed to Dr. Levine by a scientist friend of hers who knew she was adamant about funding research into SCCOHT. The fund provided Dr. Levine with initial support to ensure the sequencing could take place. “This philanthropy was key to sending us down this path,” Dr. Levine says. “We never could have made this happen through traditional funding mechanisms.”

Liz says that Katie was about to enter a premedical course of training at Johns Hopkins University when she was diagnosed. Katie was shocked to find that there was very little information available about SCCOHT and vowed that something needed to be done to shed light on the disease.

“I know that had Katie lived she would have done something for this research,” Liz says. “For me, it helps her to be alive. I’m very pleased with the results of this study and know it was not an easy thing to pull off. I’m excited and hopeful we will be able to do more.”

Dear Ishan, we are sorry to hear of your mother’s diagnosis. If she would like to make an appointment with a physician at Memorial Sloan Kettering, please ask her to call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

Jane Enter

Oct 20, 2014 • 4:42 AM

My 18 yr old daughter was diagnosed with SSCOHT in Jan 2013. The tumour was in her left ovary, 15 cms and Georgia had hypercalcaemia. Georgia underwent 5 rounds of week long, every 3 weeks, chemotherapy consisting of cisplatin and ectopiside. There was no spread when the cancer was found but the area the tumour had rested on - had reddening. Georgia saw an excellent oncological-gynaecological surgeon who removed the ovary and the reddening. A pet scan showed no spread. Georgia's cancer was staged 2C. The chemo showed good response- CA 125 markers dropped to within normal range. 4 weeks after chemo stopped Georgia was about to begin radiotherapy when she had pain in her pelvis. Surgery which was supposed to re- locate her remaining ovary to protect it from the radiotherapy, showed rapid growth and spread of the cancer. Georgia went onto have maximum allowed radiotherapy as well as being debulked. Georgia died 8 months after diagnosis. We sent Georgia's tumour to Dr. William Foulkes at McGill in Canada. We sent blood samples to from myself and Georgia (the blood was taken when Georgia was still alive ) . The research showed no genetic predisposition or inherited gene mutation issues. But it did show the same SMARC -4 problem . My question is what causes these mutations if not inherited and could the Gardisil HPV vaccine be a factor in causing the mutation? Or what carcinogens could have caused the mutation? We live in a pollution free area, Georgia was mostly vegan, did smoke sporadically for a few years on weekends and was physically fit and active. Why did her normal body surveillance system fail to recognize the carcinoma cells? I am trying to understand why Georgia got this cancer. Any ideas would be very useful. Thank you, Jane Enter.

Jane, our deepest condolences for the loss of your daughter. We sent your questions to Dr. Levine and he responds:

“There is no evidence that an HPV vaccine would be related at all to a sporadic mutation in SMARCA4. We do not know what is causing these tumors to develop mutations in SMARCA4, but are actively looking for ways to create new treatments. Our initial approaches will revolve around identifying what is required to sustain the tumor when the SMARCA4 gene and protein do not function properly. Unfortunately, most aggressive cancers find ways to avoid the normal body surveillance systems.
We do not know at present why some young women develop this very rare and aggressive cancer, but have other studies trying to figure that out too.”

James Knost

May 17, 2015 • 11:52 AM

We have seen two cases of SCCOHT in the last year and have been working with William Foulkes.
I would like to advance a SCCOHT study group to address some of the very difficult decisions that this mutation presents in affected and unaffected patients i.e. prophylactic oophorectomy in young women, penetrance , associated malignancies. Has this already been launched?

James, thank you for reaching out. We passed your question on to Dr. Levine, and he responds:

There is a patient advocate group on Yahoo that has set up a patient collection survey to try and collect information from as many patients as possible. There are also several groups working together to develop a prospective clinical trial. I am not aware of any integrated groups that are addressing the specific question that you raise. I did recently learn that Ambry Genetics is offering SMARCA4 germline testing as part of their ovarian cancer panels and this is a great step forward to have a commercial laboratory that can do testing for affected families.

Crystella

Feb 5, 2017 • 10:47 AM

Hello,
I was tested after my mother died of cancer; thought to have started in the ovaries. Ive had hormone issues since puberty and was diagnosed with P.C.O.S. just last year.
The genetic blood test showed I have the smarka4 mutation. Ive have my ca125 checked once and will continue to do so every six months. I want to be a part of this research! I believe our diet and lifestyle can largely influence how this cancer develops. I want my information shared with the researchers. Please give me tips on what to do next to share my test results, lifestyle and such.

Dear Crystella, we’re very sorry for the loss of your mother. We recommend you talk to your healthcare team about any recommendations they may have for lifestyle changes, based on your particular circumstances. Thank you for sharing your experience with us, and best wishes to you.

Donna Downing For Stephanne My Daughter

May 22, 2017 • 1:27 PM

My daughter Stephanne is hopefully leaving for the trail at Sloane Kettering Monday. Her story is the same as everyone above. Prayers that she makes the trial.. xoxo